Neural Subtype Specification from Human Pluripotent Stem Cells

Abstract

Summary Human pluripotent stem cells (hPSCs) provide a model to study early neural development, model pathological processes, and develop therapeutics. The generation of functionally specialized neural subtypes from hPSCs relies on fundamental developmental principles learned from animal studies. Manipulation of these principles enables production of highly enriched neural types with functional attributes that resemble those in the brain. Further development to promote faster maturation or aging as well as circuit integration will help realize the potential of hPSC-derived neural cells in disease modelling and cell therapy.

Advances in Zika Virus Research: Stem Cell Models, Challenges, and Opportunities

“…It is not clear how other areas could be affected. Protocols have been established to differentiate human pluripotent stem cells into neural lineages corresponding to different CNS regions in both monolayer cultures (Tao and Zhang, 2016) and as brain organoids, including forebrain, midbrain, hypothalamus, retina, and heterogeneous organoids of multiple brain regions (Kelava and Lancaster, 2016). On the other hand, we need to be aware of limitations of current stem cell-based models, such as a lack of any immune cells or blood vessels for natural viral delivery.…”

“…The last decade has witnessed tremendous progress in the stem cell field. It is now possible to derive iPSCs from patients with various disorders and differentiate them into various cell types in two-dimensional monolayer cultures (Tao and Zhang, 2016), or into three-dimensional organ-like tissues named organoids (Clevers, 2016). Stem cells have been used to investigate the basic biology of organ development, model human disorders, screen therapeutic compounds, and develop cell replacement strategies.…”

Antagonism between the transcription factors NANOG and OTX2 specifies rostral or caudal cell fate during neural patterning transition

“…The mostly used method to induce neural differentiation in hPSCs is through suppression of both TGFβ and BMP signaling (17,18). Dual-inhibition of SMAD-dependent TGF-β and BMP signaling by their inhibitors (SB431542 and Noggin), or SB431542 and Dorsomorphin can efficiently trigger hPSCs differentiation into NPCs (19-21).…”

Stem Cells, Genome Editing, and the Path to Translational Medicine

“…The approach entails the derivation of hPSCs with known disease-associated mutations followed by in vitro differentiation into disease-relevant cell types. Differentiation into all major cell types of the CNS including a wide variety of specific neuronal subtypes, such as astrocytes, oligodendrocytes and more recently microglial cells (Muffat et al, 2016), can be induced with great precision (reviewed in (Tao and Zhang, 2016)). Using such in vitro generated cells in disease modeling may uncover alterations in molecular and cellular phenotypes associated with a specific disease, which can subsequently reveal detailed mechanistic insights and guide the development of novel therapeutics.…”

“…The traditional protocols for in vitro differentiation recapitulate the order and timing of regional specification and neuronal commitment during embryonic development by supplying developmental cues like morphogens or modulating developmentally relevant pathways using small molecules (Keller, 1995). This approach can direct cell fates with remarkable precision to all major cell types of the nervous system including various distinct neuronal sub-types resembling dopaminergic, glutamatergic, GABAergic, motor, hypothalamic and striatal medium spiny neurons (Figure 3) (Tao and Zhang, 2016). However, differentiation outcomes may suffer from substantial clone-to-clone variability, adding a significant source of variability to cellular disease models (Soldner and Jaenisch, 2012).…”